Coenzyme Q10 formulation and process methodology for softgel capsules manufacturing

ABSTRACT

A formulation of Coenzyme Q 10 , beta-carotenes, Vitamin E, and medium chain triglycerides in rice bran oil and an optional thickener, such as bee&#39;s wax, is provided in a soft gel capsule so that a maximum of the Coenzyme Q 10  is absorbed by the human body. Generally, about 60 mg of Coenzyme Q 10  is the normal amount provided daily to a healthy sedentary adult.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.09/536,597, filed on Mar. 28, 2000 now U.S. Pat. No. 6,616,942 whichclaims priority from U.S. Provisional Application Ser. No. 60/126,656,filed Mar. 29, 1999, the contents of which are herein incorporated byreference in their entirety.

BACKGROUND OF THE INVENTION

This invention relates to an improved formulation and processmethodology of Coenzyme Q₁₀ in producing soft gel capsules of thisformulation. Coenzyme Q₁₀(CoQ₁₀ or Ubiquinone) is a large molecularweight (863.63 grams) lipid compound that is produced in the liver andperhaps other body organs. The total body content is estimated to be 1.4to 1.8 grams, depending on the age and the physical fitness of theindividual. Although CoQ₁₀ is found in the mitochondria and otherorganelles of every living cell, it appears to be most abundant intissues with a high number of mitochondria and a high level of metabolicactivity. For example, in the metabolically inactive blood there isapproximately 4 mg, in the heart, and in the skeletal muscle 1000 mg.The blood acts as a CoQ₁₀ reservoir and transport media betweenendogenous CoQ₁₀ synthesis in the liver, exogenous CoQ₁₀ absorption fromdigested food substances in the intestinal tract, and the body cells.Endogenous synthesis appears to be responsible for 56 percent andexogenous sources for 44 percent of the body's CoQ₁₀ requirements. Thesenumbers are currently being studied and endogenous CoQ₁₀ synthesis maybe significantly deficient in the elderly. These deficiencies are notrelated to the total caloric intake, but rather to the vitamin contentof ingested foods. The body requires multiple vitamins for the synthesisof CoQ₁₀.

CoQ₁₀ requirements of the body are also variable between individuals andare dependent on age, physical activity, and disease. It is estimatedthat the body CoQ₁₀ utilization is between 5 and 9 mg per day.Intercellular CoQ₁₀ is required for the synthesis of energy andtherefore essential for life. Energy synthesis occurs in themitochondria, where CoQ₁₀ provides an electron for the electrontransport chain in the cytochrome system, in which adenosinetripohosphate (ATP) is synthesized. As CoQ₁₀ gives up an electron forATP synthesis, it gets oxidized. If CoQ₁₀ is used as an antioxidant, itgets oxidized and is no longer available to provide electrons andfunction in the synthesis of ATP. Under conditions of high metabolicstress, endogenous sources may become inadequate to meet the body'sCoQ₁₀ requirement for ATP synthesis. Under such conditions, dietaryCoQ₁₀ supplementation has been shown to be an effective source. Animproved soft gel formulation and process of CoQ₁₀ soft gel capsulemanufacturing has uses to treat heart failure, chronic fatigue andpatients with psoriasis and planter warts. In all cases, it has beenfound that the improved soft gel formulation at ingestion rates of30–100 mg/day of CoQ₁₀ have been proven to be superior to commerciallyavailable 60 mg dry powder capsules, and existing 100 mg/day CoQ₁₀ softgel formulations.

An appropriate CoQ₁₀ dosage for a normal individual compared to thedosage necessary for a diseased individual has been difficult toascertain. Recommended doses of 10 to 30 mg/day were found to beineffective for patients with significant CoQ₁₀ deficiencies. In thepast 15 years, it has become generally accepted that poor intestinalabsorption of certain CoQ₁₀ formulations limits their effective use. Forthis reason, 50 and 150 mg CoQ₁₀ containing tablets or capsules arecommercially available to the consumer, at a considerably higher cost.

Folkers et al (U.S. Pat. No. 4,824,669) addresses a soft gel capsulewith CoQ₁₀ and at least one vegetable oil. This formulation wasdetermined to increase blood CoQ₁₀ levels to 2.5 μg/ml compared to 1.6μg/ml for an equivalent 100 mg dose of dry powder CoQ₁₀. Many differentCoQ₁₀ formulations have appeared which are claimed to increaseintestinal absorption. However, intestinal absorption data, collectedunder near basal conditions, which compare CoQ₁₀ alone in oil with drypowder CoQ₁₀, are conclusive that oil is a better delivery agent.

SUMMARY OF THE INVENTION

The present invention comprises a stable and nontoxic soft gel CoenzymeQ₁₀ formulation and process methodology of Coenzyme Q₁₀ for maximumCoenzyme Q₁₀ levels in the human body for a given input. A preferredsoft gel formulation includes Coenzyme Q₁₀ (hereinafter CoQ₁₀), VitaminE, beta-carotene, bee's wax, medium chain triglycerides available as MCTMyglyol S12, and rice bran oil formulated to maximize the body'sabsorption by maintaining the CoQ₁₀ in what may be a supersaturatedsolution in easily absorbed materials, that can provide healthfuleffects, as opposed to just fillers. It is important as much of thesupplied CoQ₁₀ be absorbed, rather than just taking megadoses atfrequent intervals as the wholesale cost of CoQ₁₀ dry powder in quantityis as much as $2000 per kg. Not only is a relatively large percentage ofthe CoQ₁₀ absorbed, but the volume of the soft gel capsule is minimized,making it easier to swallow and requiring smaller shipping and storagespace. Recent studies indicate the preferred soft gel CoQ₁₀ formulationshould be administered twice a day in dosages of about 30 mg CoQ₁₀ in220 mg capsules, as that amount of CoQ₁₀ is about the maximum the bodyof a healthy sedentary adult can use for maintenance of a preferredblood level. For those who have deficiencies of CoQ₁₀, studies haveshown that twice a day administration of about 60 mg CoQ₁₀ in 435 mgcapsules is advantageous. In special instances of CoQ₁₀ deficiency,twice a day ingestion of 100 mg CoQ₁₀ containing soft gel capsules canbe tolerated.

It is therefore an object of the present invention to provide a soft gelformulation of CoQ₁₀ and a methodology of formulation processing thatproduce a significantly greater bioavailability percentage of ingestedCoQ₁₀ than existing soft or dry formulations.

Another object of the present invention is to provide a soft gelformulation of CoQ₁₀ and methodology of administration that producesgreater absorption of CoQ₁₀ into the intestine.

Another object is to minimize the ingested volume required to maintain agiven CoQ₁₀ blood content.

Another object is to provide a process that keeps CoQ₁₀ in solution inreadily absorbed materials, that themselves have beneficial effects.

These and other objects and advantages of the present invention willbecome apparent to those skilled in the art after considering thefollowing detailed description of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The unique formulation of the present invention of a stable andnon-toxic soft gel Coenzyme Q₁₀ where the amount of Coenzyme Q₁₀ isbalanced with antioxidants and absorption agents to maximize thepercentage of Coenzyme Q₁₀ in a capsule of a given size, that isdelivered to the blood stream from the intestines. The formulationincludes: Coenzyme Q₁₀, Vitamin E, beta-carotene, bee's wax, mediumchain triglycerides (MCT) such as MCT Myglyol S12, and rice bran oil.The preferred soft gel Coenzyme Q₁₀ formulation of the present inventionis prepared in accordance with the following sequence of ingredients andprocess.

Rice bran oil, a carrier suspension agent for soft gel formulationuseful for absorption of lipophilic ingredients such as Coenzyme Q₁₀, isheated to 50 to 60° C. Bee's wax is then added. 50° C. is above themelting point of bee's wax and the wax and oil is mixed until a uniformmixture is formed. Bee's wax thickens the rice bran oil and acts as asuspension agent for subsequent ingredients. Without bee's wax, theother ingredients, which are to suspended inside a transparent gelcapsule, might separate or congregate under the effect of gravity, andappear faulty or spoiled to the consumer.

Subsequently, the mixture is cooled to 35 to 45° C. Coenzyme Q₁₀,beta-carotenes including alpha and beta carotenes, cryptoxanthin, luteinand zeaxanthin (available commercially as Betatene, available fromCognis Nutrition), Vitamin E, and medium chain triglycerides (MCT) arethen simultaneously added to the oil-wax mixture under a vacuum (toeliminate oxidation) and mixed together for one to two hours.beta-carotenes improves the solubility and adds antioxidant value.Vitamin E is an antioxidant preservative that prevents peroxidation ofthe final product, adds antioxidant value, and is fat soluble. AlthoughVitamin E is available commercially in 30 IU, 100 IU, 200 IU, 400 IU,and 1000 IU concentrations, for the present invention concentrationsfrom 350 IU to 400 IU are usable, with 372 IU being the preferredconcentration, which results in a concentration from 30 to 100 IU in thesoft gel capsule. Medium chain triglycerides are fatty acids thatimprove the lipid environment and enhance absorbibility like the ricebran oil. The bee's wax primarily increases viscosity to keep insolublecomponents from settling to one side of the soft gel capsule, but italso improves solubility. For instances where viscosity (and in turn gelcapsule cosmetics) is not a concern, it can be eliminated.

The resultant mixture is cooled to 25 to 30° C. A nitrogen gas blanketis introduced to shield the mixture for oxygen and the pressure isreturned to atmospheric. The mixture is then encapsulated in a soft gelcapsule.

Formula 1 Ingredient Amount Range % in formula 1. Vitamin E 372 IU 0.161g–2.50 g 37%–51% 2. Beta Carotene 0.00525 g–0.118 g 1.2%–2.5% (20% fromD. salina) 3. MCT Myglyol 812 0.5 g–1.0 g 12%–21% 4. Rice Bran Oil 0.193g–.50 g 10%–44% 5. Yellow Bee's Wax 0.015 g–.2 g 1%–4% 6. CoQ₁₀ 0.5–2.0g 10%–15%

Formula 2 Ingredient Amount Range % in formula 1. Vitamin E 372 IU 0.161g–2.50 g 38.5%–53%   2. Beta Carotene 0.00525 g–0.118 g 1.25%–2.6%  (20%from D. salina) 3. MCT Myglyol 812 0.5 g–1.0 g 12%–22% 4. Rice Bran Oil0.193 g–.50 g 10%–46% 5. CoQ₁₀ 0.5–1.0 g 11%–16%

The bioavailability or intestinal absorption of CoQ₁₀ has been a majorcontroversy in the international CoQ₁₀ research community. Previous dataindicate that only 1 to 3 percent of dry powder CoQ₁₀ formulations areabsorbed through the lacteals in the intestines and appear in the bloodover a twelve hour interval. In general, blood levels of 1.2 to 1.6μg/ml have been reported, when taking 30 to 60 mg/day dry powder CoQ₁₀formulation for 30 days. It has been reported that when a dry powderCoQ₁₀ formulation is taken with a fat, such as peanut butter,steady-state blood levels of 2.0 to 2.8 μg/ml are measurable.

Multiple clinical trials were conducted in the United States and Europeusing the Folkers (U.S. Pat. No. 4,824,669) soft gel. With a dosage of100 mg/day, multiple investigators have reported group mean blood levelsof 2.3 to 3.5 μg/ml depending on the laboratory conducting themeasurement.

As observed in recent trials, the bioavailability results found for thepresent soft gel indicate it provides approximately 50 percent, and withtwo 30 mg CoQ₁₀ containing capsules, 100 percent, of the daily CoQ₁₀requirements of a normal sedentary individual. It would take at leastthree of the dry powder 30 mg CoQ₁₀ capsules to produce the same effectsas one soft gel, and six to produce the same effect as two 30 mg CoQ₁₀containing soft gel capsules of the present invention. Regardless of theabsorption mechanism, the significantly higher basal blood CoQ₁₀ levels(167%) and the 273% greater absorption rate were found in previousstudies to establish that the present soft gel formulation is indeed asuperior product to dry CoQ₁₀ formulations. This may be particularlytrue for those individuals whose daily CoQ₁₀ requirement is elevated dueto high physical activity, an increased use of CoQ₁₀ as an antioxidant,and disease associated with known CoQ₁₀ deficiencies.

Cellular CoQ₁₀ content is a function of the number and quality of thecellular mitochondria. For example, the failing heart muscle has 2.2 μgCoQ₁₀ per mg of tissue and a blood CoQ₁₀ deficiency of 0.3–0.5 μg/ml.The normal hearts conditioned heart has 6.3 μg/gm per mg of tissue, anda low basal blood level of 0.5–0.6 μg/ml. These results indicate thatsupplemental CoQ₁₀ enters the cell. This observation has also beenreported for skeletal muscles of trained and non-trained athletes.

The subjective and objective responses to supplemental CoQ₁₀ in thenormal individual appear more rapidly compared to that of the physicallyunfit or the diseased individual with a CoQ₁₀ deficiency. The mostprobable reason for this observation is that the metabolic machinery(mitochondria) is viable in the non-diseased normal volunteer, whereasthe mitochondria are atrophied in the cells of deconditioned and/ordiseased individuals. Therefore, it takes time in the diseasedindividual to build up the mitochondria to a more normal activity leveland to normalize their distribution in the organ system involved.

In summary, studies have statistically proven that the present soft gelCoQ₁₀ formulation used at 60 mg CoQ₁₀/day is superior to dry powderCoQ₁₀ formulations, and prior art soft gel formulations.

Thus, there has been shown novel formulations, which fulfill all of theobjects and advantages sought therefor. Many changes, alterations,modifications and other uses and applications of the subject inventionwill become apparent to those skilled in the art after considering thespecification. All such changes, alterations and modifications which donot depart from the spirit and scope of the invention are deemed to becovered by the invention which is limited only by the claims thatfollow.

1. A method of producing a soft gel capsule for delivery of Coenzyme Q10into a human body including: heating rice bran oil to at least 50° C.then adding: Coenzyme Q10; beta-carotenes; Vitamin E; adding bee's waxto the heated rice bran oil; mixing the bee's wax and the rice bran oiland adding medium chain triglycerides to the heated rice bran oil undera vacuum; mixing the resultant mixture for at least 1 hour; cooling themixed resultant mixture to at least 30° C.; shielding the cooled mixedresultant mixture with nitrogen while returning the cooled mixedresultant mixture to atmospheric pressure; and encapsulating the cooledmixed resultant mixture in a soft gel capsule.